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132 Cards in this Set

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List 4 ways cells can be resistant to Alkylating agents
1. Impermeable to drug, pump drug out
2. Alternate targets for drug (Glutathione = reacts with agent)
3. Increased DNA repair
4. No Apoptosis = loss of p53
Adverse Effects of Alkylating Agents:
1. Target these 3 rapidly growing cells
2. Dose-dependent toxic effect causes decreased ____ and ___
3. Maximum suppression is ______ after therapy
4. Recovery is ______ after drug
5. Monitor patient tolerance by _____ and ____
1. Bone Marrow, GI tract, Spermatogenesis

2. Leukocytes and Platelets

3. 10 days to 4 weeks

4. 3 to 6 weeks

5. CBC and Hematocrit
Secondary Malignancy:
Most chemical carcinogens act by _______ of nuclear DNA, leading to altered structure and function
Covalent modification

***Alkylating agents
The concern of Secondary Malignancy is Proportional or Inversely Proportional to the age of the patient?
Inversely Proportional = the younger the patient, the more concern
Alkylating agent that is a nitrogen mustard and was the 1st alkylating agent
Mechlorethamine
Alkylating agent that is only administered IV b/c it produces blisters and is caustic to skin and mucous membranes
Mechlorethamine
How is Mechlorethamine often administered to target its site?
In the arterial supply directly to the tumor
Alkylating agent whose half-life is several minutes, reacts and breaks down rapidly in water and salt.

Used to treat Hodgkin's Lymphoma
Mechlorethamine
What are the acute adverse effects of Mechlorethamine?
Nausea and vomiting
What are the delayed adverse effects of Mechlorethamine?
Decreased blood counts
- minimum levels 10-12 days after administration
- Recovery = 3-6 wks
What is the primary use of Mechlorethamine?
Hodgkin's disease

**part of MOPP
-Mechlorethamine
-Oncovin = Vincristine (VCR)
-Procarbazine
-Prednisone
What are the 2 Nitrosourea alkylating agents?
Carmustine (BCNU)

Lomustine (CCNU)
Alkylating agents that are activated NON-ENZYMATICALLY, are LIPID-SOLUBLE and CROSS the BBB

Primary use is BRAIN TUMORS
Nitrosureas
-Carmustine
-Lomustine
Why are the Nitrosureas primarily used for Brain Tumors?
because they are lipid-soluble and can cross the BBB
How are the Nitrosureas administered?
IV or Direct Implant
What are the 2 adverse effects of Nitrosureas?
GI

Myelosuppression
One of the most widely used Alkylating agents mostly b/c it can be given ORALLY
Cyclophosphamide

*also given via IV
Alkylating agent that is not intrinsically active, but must be activated by Liver P450's = good ORAL drug
Cyclophosphamide
What are the acute adverse effects of Cyclophosphamide?
Nausea and vomiting
Alkylating agents with these ADR's:
1. Bone Marrow depression (moderate)
2. Alopecia
3. Sterile Hemorrhagic Cystitis
Cyclophoshamide
Metabolic product of Cyclophosphamide that causes Sterile Hemorrhagic Cystitis
Acrolein = reactive and water soluble molecule that gets excreted in urine
- reacts with components of the epithelium and you get bleeding
What are 2 things that can be done to prevent Sterile Hemorrhagic Cystitis with Cyclophosphamide?
1. Over-hydrate before giving drug = quicker washing out when given

2. Mesna = thiol which reacts with Acrolein in urine
Bifunctional "platinating agent" = cross-links DNA
Cis-Platin
-binds to 2 different bases and cross-links them
Cisplatin:
-Administered?
-Excreted?
1. IV

2. Urine
Cisplatin is relatively non-toxic to ________
bone marrow
What are the 2 acute adverse effects of Cisplatin and what is done to minimize them?
1. SEVERE nausea and vomiting = use HT3 antagonists

2. RENAL Toxicity = ensure adequate hydration
Platinum complex that causes:
-less nausea and renal toxicity than Cisplatin
-but more myelosuppression
Carboplatin
Platinum complex that is has less renal toxicity than Cisplatin, but is neurotoxic
Oxaliplatin
Alkylates DNA and also causes strand scission (separation) = blocks DNA and RNA synthesis

Strongly Leukemogenic and Teratogenic
Procarbazine
Procarbazine shows "standard" alkylating toxicities (NVD, bone marrow depression), but it also has these adverse effects
1. Leukemogenic = causes leukemia

2. Teratogenic = causing malformation of fetus
What is the mechanism of Anti-cancer Anti-metabolites?
-Analog of a normal component of the target cell
-enters into a normal metabolic pathway, but then BLOCKS that pathway
Anticancer antimetabolite that is a Dihydrofolate Reductase (DHFR) substrate and inhibitor
Methotrexate = Folic acid analog
What are the 2 advantages of Methotrexate being polyglutaminated in mammalian cells?
1. can help it stay in the cells
2. there are steps that are more effectively inhibited by methotrexate derivatives
What does Methotrexate decrease the synthesis of?
THF and therefore Thymidine = decreased DNA and protein synthesis
Methotrexate:
1. Administration
2. Excretion
3. Cell cycle phase specificity
1. Orally, IV, Intrathecally

2. Urine

3. S phase
Describe "rescue therapy" using Methotrexate
Give high dose to have maximum effect on tumor cells, "rescue" normal cells by giving Folinic Acid (Citrovorin, Leucovorin)
What cell cycle phase is Methotrexate only effective in?
S phase
Folate antagonist that with chronic use can cause Hepatotoxicity = fatty liver
Methotrexate
What are the 2 Folinic Acid drug names that can be given in Methotrexate "rescue"?
Citro-vorin

Leuco-vorin
What are 3 ways tumors can become resistant to Methotrexate?
1. decreased drug accumulation
2. amplified DHFR
3. altered DHFR
What are the 2 Antimetabolite Purine Antagonists?
1. 6-mercaptopurine

2. 6-thioguanine
6-MP and 6-TG:
1. Administration?
2. Well-tolerated, but this happens only at high doses
1. Oral

2. Bone Marrow depression
Purine antagonist that inhibits AMP and GMP synthesis = blocks DNA and RNA synthesis
6-Mercaptopurine
Anti-tumor Purine antagonist that is incorporated into RNA and DNA, altering function
6-thioguanine
The 2 ways tumor cells become resistant to these 2 drugs is by:
1) a decrease in HPRT activity
2) increase in Alkaline Phosphatase
6-Mercaptopurine

6-Thioguanine
What are the 2 Antimetabolite Pyrimidine Antagonists?
5-fluorouracil

Cytarabine
T or F: Purine analogs are far more toxic than Pyrimidine analogs
False: Pyrimidine analogs are more toxic = Bone Marrow, GI
Pyrimidine Antagonist that inhibits Thymidylate Synthase (inhibits conversion of dUMP to dTMP)
5-Fluorouracil
What is 5-Fluorouracil's activity enhanced by?
Folinic Acid (Leukovorin)

*Leukovorin also "rescues" Methotrexate toxicity
Cytosine analog, chain terminator used as an anti-cancer drug
Cytarabine
Anti-tumor Antimetabolites that is bioactivated by HGPRTase
6-Mercaptopurine
What is the connection between Flucytosine and 5-fluorouracil?
Flucytosine is bioactivated into 5-FU in Fungal cells = inhibit Thymidylate synthase
What are the 2 Vinca Plant Alkaloid drugs?
1. Vinblastine

2. Vincristine
What are the Vinca Alkaloids isolated from?
Vinca Rosea = Periwinkle
What is the mechanism of action of the Vinca Alkaloids?
Inhibit/reverse tubulin polymerization = disrupts mitotic spindles
What do Vinca Alkaloids cause?
Metaphase Arrest
Vinca Alkaloids:
1. Administration?

2. Excretion?
1. IV = due to large size

2. Biliary excretion
What is Vinblastine's adverse effect?
1. NVD
2. Alopecia
3. Bone marrow depression

*vinBLASTin BLASTs Bone marrow
Why is Vincristine's use limited to short duration?
Peripheral neuropathy = MT's that we are blocking for therapeutic effect are also blocking transport within the long axons of nerves
What are the 2 Podophyllotoxin Plant Alkaloids?
1. Etoposide (VP-16)

2. Teniposide

**-POSIDE's
What is Etoposide/Teniposide's mechanism of action?
Topoisomerase II inhibitors = end up with DNA molecules with double strand breaks that are pretty much impossible to repair

Also marks DNA for degradation
What stage does Etoposide/Teniposide arrest cells in?
S-G2 stage
Etoposide/Teniposide:
1. Administration

2. Adverse effects
1. Oral and IV

2. N/V, Alopecia, BM suppression
What are the 2 Camptothecin Plant Alkaloids?
Top-otecan

Irin-otecan
Anti-tumor agents that are Topoisomerase I inhibitors
Topotecan & Irinotecan

**-TECAN's = TOPO I inhibitors
Topotecan/Irinotecan:
Administration?
IV
Plant Alkaloids these ADR's:
-Mucositis
-Severe diarrhea
-Cholinergic syndrome = salivation, cramping***which one specifically?
Topotecan

Irinotecan --> Cholinergic syndrome
What are the 2 Taxane Plant Alkaloids?
1. Paclitaxel (Taxol)

2. Docetaxel (Taxotere)
Antitumor agents that STABILIZE microtubules so that the mitotic spindle cannot break down
Paclitaxel & Docetaxel

**-TAXOL's
What phase of the cell cycle are -Taxel's specific for?
M phase
What are the acute adverse effects of -Taxels?
Hypersensitivity

Nausea

*probably due to Cremophor
What are the delayed adverse effects of Taxanes?
BM suppression

Some neuropathy
Antitumor agents that are administered via IV in Cremophor (solubilizing agent) and show promise against solid tumors
Paclitaxel & Docetaxel
What are most antitumor antibiotics produced by?
Microbes -> Streptomyces
Antitumor antibiotics interact with DNA and/or RNA, but most do not ______
alkylate
How are all Antitumor Antibiotics administered?
IV
What drugs are in the Anthracycline antitumor antibiotics category
-rubicin

Doxorubicin, Daunorubicin
Anti-tumor Antibiotics that:

Intercalate into DNA and slide between adjacent bases = block Topoisomerase II, inhibit DNA and RNA synthesis, cause strand breaks

Generate free radicals
-Rubicin's = Daunorubicin & Doxorubicin
How are the -rubicin's cleared?
Metabolized in liver
The "signature" ADR of these drugs is CARDIOTOXICITY
Daunorubicin & Doxorubicin

= -Rubicin's
What is the Cardiotoxicity of Anthracyclines a function of?
Cumulative dose
Cardiotoxicity of Anthracyclines:
-may be exacerbated by __1__
-complications: __2__
-mechanism: __3__
1. radiation
2. arrhythmias, cardiomyopathy, CHF
3. free radicals
What is the Cardiotoxicity of Anthracyclines minimized by?
Dexrazoxane
Antitumor antibiotic that is a mixture of glycopeptides that complexes with Fe and O2 -> generates free radical -> causes DNA strand breaks
Bleomycin
When is Bleomycin only active (what cell cycle phase)?
G2 = synthesis of components needed for mitosis
ADR's of this antitumor antibiotic are:
1. Hypersensitivity
2. Cutaneous rxns
3. PULMONARY FIBROSIS
Bleomycin
Antitumor antibiotic that is particularly effective against SOLID TUMORS
-its activation is favored by Hypoxia
-Alkylates DNA
Mitomycin C
How is Mitomycin C administered?
IV or by Bladder instillation
Antitumor antibiotic that intercalates in DNA and blocks RNA and DNA synthesis
-Used for Wilms's tumor, Ewing's Sarcoma, and Rhabdomyosarcoma
Dactinomycin (Actinomycin D)

**Actinomycin D is used for childhood tumors -> children ACT out
ADR of this antitumor antibiotic is: inflammation at sites of prior radiation = "radiation recall"
Dactinomycin
What is the function of Adrenocorticosteroids, Hydrocortisone, and Prednisone in treating cancer?
suppresses proliferation of immune cells (leukocytes, lymphocytes) = used in therapy for leukemias and lymphomas
How are the Adrenocorticosteroids, Hyrdocortisone, Prednisone administered?
Orally
What are the delayed adverse effects of Adrenocorticosteroids, Hyrdocortisone, Prednisone?
Fluid retention
Immunosuppression
Diabetes
Blocks conversion of androgens to estrogens, specific for estrogen production
Aromatase inhibitors
List the 3 Aromatase Inhibitors
1. Anastrazole
2. Letrozole
3. Exemestane
Aromatase inhibitors more effective against the Peripheral Aromatase form
-used in treatment for Estrogen receptor primary and metastatic breast cancer
Anastrazole

Letrozole

**-AZOLE's
Steroidal irreversible aromatase inhibitor
Exemestane

*no cross-resistance with azoles
What are the acute and delayed adverse effects of Exemestane?
Acute = mild nausea, headache

Delayed = Fatigue, hot flushes
Selective Estrogen Receptor Antagonist (SERM) that is an antagonist in the breast but an agonist in Endometrium, increasing the risk of Endometrial Cancer
Tamoxifen
SERM that is an antagonist in the breast, but also an AGONIST in Bone, which may work against Osteoporosis
Raloxifene
Describe the mechanism of SERM's

What group of women are they more effective in?
Competing ligands for Estrogen Receptor, but don't activate it

Post-menopausal women
What is Tamoxifen used for to treat?
ER+ Primary and Metastatic breast cancer
List 3 adverse effects of the SERM's
1. Nausea
2. Hot flashes
3. Vaginal bleeding
Name the two SERM's
Tamoxifen

Raloxifene

*-oxifen(e)
List the 2 Androgen Receptor Antagonists
Flutamide

Bicalutamide

*"-lutamide's"
2 drugs used with radiation to treat Prostate Cancer
Flutamide

Bicalutamide
What are the adverse effects of Flutamide and Bicalutamide?
Mild:
-nausea
-hot flashes
-transient hepatic effects
Explain why Asparaginase might be used in anti-cancer therapy
Depletes serum Asparagine, which is needed in large amounts by some tumors
What cancer is Asparaginase specifically used against?
Acute Lymphocytic Leukemia (ALL)

**aSPARE ALL***
Asparaginase:
1. Administration?
2. Adverse effect
1. Parenteral

2. Hypersensitivity (can be fatal!)
Antitumor agent that inhibits Ribonucleotide Reductase
Hydroxyurea
Antitumor agent that is used to treat Leukemias and SCC of the head and neck. Also has these 4 ADR's:
1. N/V
2. Mucositis
3. Rash
4. BM suppression
Hydroxyurea
Interferon-alpha:
-polypeptide cytokine produced by __1__
-__2__ administration
-alters __3__, __4__, and __5__
1. White blood cells
2. Parenteral
3. gene expression
4. antiviral
5. immnomodulatory
Antitumor agent used against these 3 tumors:
1. Hematologic malignancies
2. Metastatic Melanoma
3. Renal cell carcinoma
Interferon-alpha
What are the adverse effects of IFN-alpha?
1. Fever and chills
2. anorexia
3. weakness
Monoclonal antibody against VEGF-A, a critical angiogenic growth factor
Bevacizumab (Avastin)

**Bev-VEGF
Bevacizumab (Avastin) is combined with __1__ as a first-line therapy for metastatic __2__
1. Fluoropyrimidine
2. Colorectal cancer
Antitumor agent with these ADR's:
1. HTN
2. Thromboembolic events
3. wound healing complications
4. GI perforations
Bevacuzimab = Ab to VEGF-A
How is Bevacizumab administered?
IV
Monoclonal antibody against HER2neu/ErbB-2 oncogene product (Epidermal Growth Factor receptor)
Trastuzumab (Herceptin)
What is Trastuzumab used against?
Breast cancer whose cells overexpress HER-2
Antitumor agent with these ADR's:
1. Infusion rxns
2. Hypersensitivity (b/c we are giving a protein product)
3. **Cardiomyopathy**
Trastuzumab
How is Trastuzumab administered?
IV
What 2 cancers is Imatinib (STI-571, Gleevec) used against?
1. Chronic Myelogenous Leukemia (CML)

2. GI Stromal tumors (GIST)
Antitumor agent that inhibits these 2 things:

Bcr-Abl tyrosine kinase in CML

Kit kinase in GIST
Imatinib (Gleevec)
How is Imatinib (Gleevec) administered?
Orally
What are 3 adverse effects of Imatinib (Gleevec)?
1. Myelosuppression
2. ***Edema and fluid retention***
3. Hepatotoxicity
What does Gefitinib (Iressa) inhibit?
EGF-R tyrosine kinase
Gefitinib:
1. Administration
2. Adverse effects
1. Orally
2. Fever, Dyspnea
What cancer is Gefitinib used against?
NON-Small cell lung cancer

*Jeff S. has a non-small cell lung CA
Signal Transduction Inhibitors transform cancer from a "__1__" disease to a "__2__" disease
1. curable

2. manageable
What are the 2 Signal Transduction Inhibitors?
Imatinib

Gefitinib